CN115607557A - Application of compound as plasma kallikrein inhibitor - Google Patents
Application of compound as plasma kallikrein inhibitor Download PDFInfo
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- CN115607557A CN115607557A CN202110804990.4A CN202110804990A CN115607557A CN 115607557 A CN115607557 A CN 115607557A CN 202110804990 A CN202110804990 A CN 202110804990A CN 115607557 A CN115607557 A CN 115607557A
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- China
- Prior art keywords
- plasma kallikrein
- formula
- acid
- compound
- pharmaceutically acceptable
- Prior art date
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Abstract
The invention discloses application of a compound as a plasma kallikrein inhibitor, and particularly discloses application of a compound shown as a formula I, a formula II or a formula III or a pharmaceutically acceptable salt thereof as a plasma kallikrein inhibitor. As shown in formula I, II or IIThe compound shown in the formula I has obvious inhibition effect on plasma kallikrein, and can be used for treating or relieving diseases such as ischemic stroke, hereditary angioedema or diabetic macular edema.
Description
Technical Field
The present invention relates to the use of compounds as inhibitors of plasma kallikrein.
Background
Kallikrein-kinin system (KKS) is a complex endogenous multienzyme system consisting of prekallikrein, kallikrein, kininogen, kinin receptors, and kininogenases. KKS is an important physiological regulation system in a mammal body, widely exists in cardiovascular system, kidney system, pancreas system, central nervous system and the like, is involved in blood pressure regulation, inflammatory change, cardiovascular homeostasis, pain transmission, cytokine release, cell proliferation and the like, and is closely related to occurrence and development of certain nervous system diseases.
Kallikrein (Kallikrein) belongs to one of the members of the serine protease superfamily, widely present in vascular endothelial cells, body fluids and neutrophils, and can be classified into two types, plasma-type (Plasma Kallikrein, PK) and tissue-Type (TK) Kallikrein. PK is specifically expressed by liver cells, is mainly distributed in blood circulation, and acts on HMWK to generate bradykinin (bradykinin, BK); TK produces kallidin by acting on LMWK. The binding of kinins to their respective receptors activates downstream signaling cascades including Nitric oxide-cyclic guanosine monophosphosphates (NO-cGMP) and prostacyclin-cyclic adenosine monophosphate cAMP, triggering a wide range of biological effects including vasodilation, smooth muscle contraction and relaxation, inflammation, involvement in blood coagulation and fibrinolysis, and the like.
KKS IS closely linked with the generation and development of etiology and pathology of Ischemic Stroke (IS), and participates in the regulation of apoptosis, oxidative stress, inflammatory reaction, angiogenesis and the like. In addition, the theory of "thrombophlebitis" IS increasingly paid attention, and the occurrence and development of the disease seriously affect the degree of reperfusion of the ischemic brain area of the IS and the degree of brain injury, thereby affecting the intervention and treatment effect of the IS. The key to this theory relates to the KKS system, centered on plasma kallikrein, which not only promotes vascular permeability and inflammation through the produced bradykinin, but also activates the intrinsic coagulation cascade, centered on FXIIa, through the contact pathway, promoting thrombosis, affecting the progression of thrombosis-related inflammation.
In cerebral ischemia-reperfusion, platelets promote platelet activation and platelet glycoprotein Ib/IIa (GP Ib/IIa) function up-regulation through collagen-von Willebrand factor (vWF) -platelet glycoprotein Ib (GPIb) axes at vascular endothelial injury sites caused by ischemia, and promote platelet aggregation; meanwhile, blood coagulation factor XII (coagulation factor XII, FXII) is converted into active FXIIa by the negatively charged inorganic polyphosphate surface exposed after platelet activation, thereby starting the intrinsic coagulation cascade pathway and promoting thrombosis. Meanwhile, activated FXIIa may cleave plasma kallikrein, activating it to form PK, and then cleaving HMWK and releasing BK. After BK is combined with corresponding receptors on endothelial cells, a series of signal cascade pathways are started to damage the endothelial cells, the expression of proinflammatory factors is up-regulated, glial cells are induced and activated, and finally brain cell damage is caused.
Besides participating in the etiology and pathology of ischemic stroke, PK also relates to the etiology and pathology of hereditary angioedema, diabetic macular edema and the like.
Acteoside A01 is a water-soluble phenylethanoid glycosides compound widely distributed in plant kingdom, and is commonly found in rehmanniae radix, cistanchis herba, semen plantaginis, flos Osmanthi Fragrantis, and flos Eupatorii.
Disclosure of Invention
The invention aims to solve the technical problem of finding a compound which has an inhibitory effect on plasma kallikrein, and the inhibition of the plasma kallikrein can treat or relieve diseases such as ischemic stroke, hereditary angioedema or diabetic macular edema. To this end, the invention provides the use of verbascoside, caffeic acid and hydroxytyrosol as plasma kallikrein inhibitors.
The invention provides an application of a compound shown as a formula I, II or III or a pharmaceutically acceptable salt thereof in preparing a plasma kallikrein inhibitor:
the compound shown in the formula I is verbascoside, the compound shown in the formula II is caffeic acid, and the compound shown in the formula III is hydroxytyrosol.
The invention provides an application of a compound shown as a formula I or a pharmaceutically acceptable salt thereof in preparing a plasma kallikrein inhibitor, wherein the plasma kallikrein inhibitor is not used for treating ischemic stroke;
the invention provides application of a compound shown as a formula I or pharmaceutically acceptable salts thereof in preparing a medicament for treating plasma kallikrein related diseases, wherein the plasma kallikrein related diseases are not ischemic cerebral apoplexy;
the invention provides application of a compound shown as a formula I or pharmaceutically acceptable salt thereof in preparing a medicament for treating plasma kallikrein related diseases, wherein the plasma kallikrein related diseases are hereditary angioedema or diabetic macular edema;
the invention provides application of a compound shown as a formula I or III or pharmaceutically acceptable salt thereof in preparing a medicament for treating plasma kallikrein related diseases;
the invention provides an application of a compound shown as a formula I or III or a pharmaceutically acceptable salt thereof in preparing a medicament for treating plasma kallikrein related diseases, wherein the plasma kallikrein related diseases are ischemic cerebral apoplexy, hereditary angioedema or diabetic macular edema;
the invention provides an application of a compound shown as a formula I or a pharmaceutically acceptable salt thereof in preparing a medicament for treating hereditary angioedema or diabetic macular edema:
the invention provides application of a compound shown as a formula I or III or pharmaceutically acceptable salt thereof in preparing a medicament for treating ischemic stroke, hereditary angioedema or diabetic macular edema;
in the present invention, the compound of formula I, II or III or a pharmaceutically acceptable salt thereof may be administered to a subject by any suitable route, for example, orally.
In the invention, the compound shown as the formula I, II or III can treat related diseases by inhibiting plasma kallikrein.
The medicament of the present invention may further comprise a pharmaceutically acceptable excipient. The compound of formula I, II or III or pharmaceutically acceptable salt thereof can be made into various suitable dosage forms, such as tablet, capsule, intravenous injection, intraperitoneal injection, inhalant, aerosol, lyophilized preparation, patch, gel, spray or suppository.
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
The term "pharmaceutically acceptable" as used herein, is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts prepared from the compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the prototype of such compounds with a sufficient amount of a pharmaceutically acceptable base, in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a prototype of such a compound with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4,4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular Berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science 66 (1977), or, handbook of Pharmaceutical Salts: properties, selection, and Use (P.Heinrich Stahl and Camille G.Wermuth, ed., wiley-VCH, 2002).
The term "treatment" refers to therapeutic therapy. Where specific conditions are involved, treatment refers to: alleviating one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade leading to or causing the disorder or (b) one or more biological manifestations of the disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with the disorder, or one or more symptoms, effects, or side effects associated with the disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of the disorder or disorder.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the invention discovers that the compound shown as the formula I, II or III has the function of inhibiting plasma kallikrein.
Drawings
FIG. 1 is a graph showing the dose-dependent inhibition of plasma kallikrein enzymatic cleavage of a specific substrate by a test compound. Wherein A represents verbascoside (A01), B represents Osmanthus fragrans aqueous extract rich in A01 (containing 45% verbascoside, OFFE), and C represents positive control Leuteptin.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Verbascoside used in the examples was purchased from Kyodo super-nine eight Biotechnology Co., ltd, batch No.: wkq20042004; the purity is more than or equal to 98 percent (HPLC). Human Plasma Kallikrein (PK), HPKA-5542, was purchased from Molecular Innovations. H-Pro-Phe-Arg-AMC acetate, batch number: 1076241 from Bachem AG. Leuppeptin, lot number: 905A0210, available from Solarbio.
The instrumentation used in the examples was purchased from the following manufacturers:
an electronic balance: sartorius, BT25S; a multifunctional microplate reader: varioskan Flash model, thermo Fisher Scientific, inc.
Example 1: inhibitory Effect of verbascoside Compounds on Plasma Kallikrein (PK)
The influence of verbascoside, caffeic acid and hydroxytyrosol on PK activity is observed by using commercial plasma kallikrein and a specific fluorescent substrate thereof. Leupeptin is a broad spectrum serine enzyme inhibitor used as a positive control.
The experiments were divided into five groups: acteoside (A01) group, A01-enriched flos Osmanthi Fragrantis water extract (containing 45% acteoside, OFFE group), caffeic acid group, hydroxytyrosol group, and positive control Leupepptin group.
Determination of the inhibition rate of plasma kallikrein:
a01, OFFE and Leupeptin with different concentrations were mixed with PK (final concentration 2 nM), incubated in a Tris-HCl buffer system at 25 ℃ for 15min (50 mM Tris-HCl,250mM NaCl, 1.5. Mu.M BSA; pH 7.5), then a specific fluorogenic substrate (H-Pro-Phe-Arg-AMC; final concentration 20. Mu.M) was added, and the fluorescence intensity was measured at 480nM using a microplate reader (excitation wavelength 360 nM). The final concentrations of A01 and OFFE (μ g/mL) were: 1.0,3.0,10.0,30.0,100.0,300.0,1000.0 and 3000.0; the final concentrations of caffeic acid and hydroxytyrosol (μ g/mL) were: 1.0,3.0,10.0,30.0,100.0,300.0,1000.0,3000.0 and 5000.0; the final Leuteptin concentration (μ g/mL) was: 0.01,0.03,0.10,0.30,1.0,3.0,10.0 and 30.0.
The percentage PK enzyme inhibitory activity was calculated according to the following formula:
enzyme inhibition (%) = (a) Blank space -A Measurement of )*100%/A Blank space 。
Data analysis
Data are presented as mean ± sem. Curve fitting was performed using GraphPad Prism 8.0.1 software.
The PK enzyme inhibition rate for each test article was as follows:
IC for inhibiting PK enzyme activity by verbascoside (A01) 50 (mu g/mL) is 195.2 +/-1.02, and Hill Slope is 1.18 +/-0.03; IC of OFFE inhibiting PK enzyme activity 50 (mu g/mL) is 350.6 +/-1.03, and Hill Slope is 1.23 +/-0.04; IC for caffeic acid to inhibit PK enzyme activity 50 (mu g/mL) is 336.5 +/-1.06, and Hill Slope is 1.11 +/-0.06; IC for inhibiting PK enzyme activity by hydroxytyrosol 50 (mu g/mL) is 1431 +/-1.02, and Hill Slope is 0.97 +/-0.02; IC for inhibiting PK enzyme activity by Leupeptin 50 (mu.g/mL) was 1.01. + -. 1.04 and Hill Slope was 0.93. + -. 0.03.
In conclusion, the verbascoside, caffeic acid and hydroxytyrosol have obvious inhibition effect on the plasma kallikrein, and have important research value and application prospect on the treatment effect of the kallikrein on diseases related to the plasma kallikrein.
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